Secretion of norepinephrine by permeabilized PC12 cells can be stimulated by the addition of either calcium or GTP[S]. Stimulation of secretion by GTP[S] results from its binding to and activating a low molecular weight GTP-binding protein. This GTP-binding protein appears to interact with nucleoside diphosphate kinase (NDPK) . NDPK is encoded by nm23 genes. Both murine and human nm23 genes have been implicated in the control of tumor metastasis. For many, but not all, types of tumors, there is an inverse relationship between the level of nm23 expression and metastatic potential. Transfection of nm23 into highly metastatic cell lines reduces their metastatic potential. Nm23 genes are also thought to be involved in cellular proliferation and differentiation. NDPK catalyzes the phosphorylation of nucleoside diphosphates to triphosphates and is responsible for maintaining nucleoside triphosphate pools. The simple maintenance of nucleoside triphosphate pools does not appear to explain the involvement of NDPK in these various cellular processes, and it has been suggested that NDPK might have other activities. Last year we reported that NDPK can phosphorylate ATP-citrate lyase. This phosphorylation results from a direct transfer of a phosphate from a histidine on NDPK to a histidine on ATP-citrate lyase. We have subsequently shown that NDPK can phosphorylate a histidine on succinyl thiokinase. Several other proteins in extracts of PC12 cells also appear to be phosphorylated by NDPK. We are in the process of trying to identify these proteins. The relationship, if any, of this protein kinase activity to the effect of NDPK on metastasis and differentiation remains to be determined. We have recently found that NDPK can phosphorylate phosphatidic acid and phosphatidylinositol phosphate to give respectively diacylglycerol pyrophosphate and phosphatidylinositol pyrophosphate. Both phosphatidic acid and phosphatidylinositol phosphate play important roles in cell signaling. The phosphorylation of these phospholipids by NDPK provides a novel mechanism by which NDPK could influence cell behavior.